On December 28, 2006, the Food and Drug Administration (FDA or the agency) released three documents addressing animal cloning for public comment. These were a Draft Risk Assessment, a Proposed Risk Management Plan, and a Draft Guidance for Industry. At the request of members of the public, the initial 90 day comment period was extended for an additional 60 days, and closed on June 3, 2007.

Comments were received by FDA’s Division of Dockets Management, and were logged in according to when they were received. Once logged into the system, comments were forwarded to the staff of the Center for Veterinary Medicine (CVM), where each comment was reviewed by a member of CVM’s scientific staff. When all of the comments had been reviewed, they were divided into two overall categories: “general” comments that were relatively short, and expressed usually one or two opinions, and “substantive” comments, which tended to be longer, and provided specific recommendations or suggestions to the agency. In this Response, we summarize all of the public comments, but have concentrated our specific responses on the substantive comments. Many of these comments provided excellent recommendations to the agency, and we have incorporated those recommendations into our updated versions of the cloning documents.

We are grateful to all of the members of the public who took the time to share their views with the agency on this issue.

All comments are available for the public to review at http://www.fda.gov/ohrms/dockets/default.htm, docket number 2003N-0573. Alternatively, comments may be viewed at the Division of Dockets Management, 5630 Fishers Lane, Room 1061, Rockville, MD 20852, or by calling 301-827-6860 for assistance in finding a particular comment.

FDA received approximately 30,500 comments. Approximately 17,500 of these were form letters, and approximately 13,000 were “directed text” comments—that is, comments that appeared to be written in response to suggestions from organizations that recommended writing to the agency to support or oppose some component of the process, or comments that contained a single message, either opposed to or supporting cloning or the labeling of food from clones. Some of these letters or comments had multiple signatures either supporting or opposing the agency’s draft documents, or cloning in general, with the number of signatures totaling about 130,000. Finally, approximately 100 of the comments were substantive—that is, they were more lengthy (some approaching 50 pages), and provided detailed analyses, recommendations, or opinions either supporting or opposing the agency’s draft documents or cloning in general.

Part of our review included sorting the substantive comments into stakeholder groups so that we could understand better the concerns of these stakeholders. Eleven such groups were identified, ranging from academics to various consumer and animal health advocacy groups to professional organizations. The following provides a list of these groups including a short description of the nature of their constituents, and the number of comments in each group.

Academics, consisting of individual scientists self-identifying as members of a university or other academic institution (n = 8);

In the following section, we have categorized comments by common themes, summarized the comments from the public according to those themes, and responded to those comments. Many of the substantive comments regarding particular studies have been addressed in the revision of the Risk Assessment itself or the associated documents (i.e., the Risk Management Plan or Guidance for Industry).

The agency has responded to the public comments in the updating of the risk assessment in two ways. First, some of the comments indicated that certain points in the Risk Assessment may have been misinterpreted or not fully understood. These comments were addressed by revising relevant sections of the Risk Assessment. Many sections were re-written to clarify points in the draft, and as a result, the methods used to assess risks to animal health and food consumption risks are now described in more detail. Second, many comments provided additional scientific references on the health of clones, their progeny, or food composition. All of these references were reviewed, and those that we determined to be relevant were incorporated into the final version of the risk assessment.

The comments addressing the nature of the approach to the evaluation of animal health and food consumption risks associated with animal cloning were divided between comments that applauded the science-based approach versus those that advocated for expanding the review beyond science-based concerns to other issues such as economics, ethics, and social issues. Of the comments that were in favor of a strictly science-based approach, most indicated that the agency’s Draft Risk Assessment was comprehensive, thorough, and transparent. These comments tended to support the conclusions and recommendations of the Draft Risk Assessment, while continuing to urge the agency to maintain the transparency of the process and dialogue with stakeholders.

Other comments voiced the opinion that the agency’s science-based approach failed to address several important issues, and urged the agency to gather more information on clones and their offspring before making a final regulatory decision. Suggestions in this group of comments included additional research on animal health and food safety, a different risk management plan, periodic updates of the risk assessment, and post-market surveillance of clones and their offspring (in contrast to other comments indicating that FDA did not have the authority to engage in extensive post-market surveillance on farms). Several comments advocated the regulation of clones as new animal drugs. In particular, these comments pointed out that such an approach would allow the agency to be more proactive and effective in its call for data and their evaluation, leading to a more rigorous assessment of safety, including clearly identified opportunities for post-market surveillance.

Other comments indicated that the science-based approach, although a good first step, was insufficient to address non-science based concerns including ethics, economics, or other social issues, and raised several points that should have been considered by the agency. These concerns are presented in more detail in Section IV.

Agency Response to these Comments:

The agency has considered what it believes are the issues that it is responsible for associated with animal cloning for agricultural purposes-- the safety of the food from clones, and the health of animals involved in the cloning process. These are science-based processes. The agency is not charged with addressing non-science based concerns such as the moral, religious, or ethical issues associated with animal cloning for agricultural purposes, the economic impact of products being released in commerce, or other social issues unrelated to FDA's public health mission.

The agency indicates that it has developed a risk management plan, the proposed version of which was released for public comment at the same time as the Draft Risk Assessment. As part of that Plan, the agency commits to the ongoing monitoring of the technology, including assessing the need for updates to the risk assessment as new information becomes available, or as the technology changes sufficiently to warrant a reexamination of potential hazards and risks. With respect to continued monitoring of clones and their offspring, the agency has noted in its Risk Management Plan that there are ongoing efforts by scientific and professional societies, such as the International Embryo Transfer Society, to survey these animals, maintain records of their health, and provide information on food products derived from clones and their progeny.

With respect to post-market on-farm surveillance of clones and their progeny, FDA, for purposes of enforcing the Federal Food, Drug, and Cosmetic Act, has authority to inspect any establishment where food or feed is held for introduction into interstate commerce or after introduction into interstate commerce. FDA would be able to use such authority if it became aware of possible adulteration or misbranding of food or feed from the clones or their progeny. However, just as a matter of routine surveillance as a part of its inspectional programs, FDA has no plans to conduct such surveillance of clones and their progeny.

With regard to the regulation of clones, to the extent that animal clones are not new animal drugs, the agency has no basis to require their compliance with the new animal drug provisions of the Federal Food, Drug, and Cosmetic Act. To the extent that animal clones meet the necessary statutory requirements to be regulated as new animal drugs, at this time, FDA intends to exercise its enforcement discretion. We note that FDA does not actively regulate all products that may fall within its jurisdiction. We consider a number of factors in determining the appropriate regulatory/enforcement strategy we will use for various products and sometimes decide to exercise enforcement discretion. We do not believe that clones of non-food species present any public health concerns. Such animals do not introduce any new heritable traits into other animals, and such clones are already in distribution or being used for preservation of endangered species. For clones of food-producing species, our intent to exercise enforcement discretion is based on (i) the conclusions in the Risk Assessment that edible products from cattle, swine, and goat clones and the progeny of all clones are just as safe as products from conventionally bred animals, and (ii) our observation that the voluntary moratorium has been sufficient to protect the public health during the agency's evaluation of clones of food-producing species and our conclusion that a continuation of the voluntary moratorium is sufficient to protect the public health as to species other than cattle, swine, and goats. See Guidance for Industry #179.

Several of the comments commended the agency for the outstanding job it had done in developing the framework it had developed, organizing the data, and interpreting it. Other comments indicated that FDA did the best job possible given what they perceived as inappropriate regulatory authority for the regulation of these animals (see Section A). Others opined that the agency shouldn’t make decisions on food safety on what they considered an inadequate number of studies, while others criticized the agency for its allegedly biased analysis. Finally, some comments requested another review by the agency’s Veterinary Medicine Advisory Committee (VMAC) prior to issuing a final report.

Agency response to these comments:

The agency notes that when the issue of animal cloning was first undertaken, there were no existing risk assessment paradigms with which to evaluate the safety of food from clones or their progeny. In order to develop the approach presented in the Draft Risk Assessment, the agency drew on the expertise of its experts in food safety, animal health, toxicology, physiology, molecular biology, and risk assessment to develop a comprehensive and rigorous approach to evaluate all of the available data on clones, their progeny, and the food from those animals. This approach was presented to the Center’s VMAC three years prior to the release of the draft document, and the VMAC agreed with the overall approach. In addition, the draft documents were reviewed by an external peer review committee prior to their release, and this committee also concluded that the approach employed by the agency was appropriate.

One of the key features of the approach developed and used by the agency is that it relies on a “weight of evidence” evaluation—that is, instead of developing a threshold number or type of studies, the analysis considered all of the information available at a particular time, and made a determination on the overall body of information considered as a whole. We explicitly described the risk assessment method, and articulated the criteria by which we would evaluate the information in the risk assessment. In particular, we pointed out that this approach took place in four smaller steps that can be divided into two overall parts. In the first part, the agency evaluated the empirical evidence (all of the data), and took into consideration the biological assumption that epigenetic dysregulation would be the source of the potential hazards to animal health and food consumption. Although the first part was concerned with evaluation of individual studies, the second part involved looking at the data and information as a whole—that is, determining whether the data are coherent with predictions based on biological assumptions (do they make sense with known biological mechanisms and principles?) and whether the data are consistent (do you see the same kinds of responses in similar situations?). It is these last two steps, which serve as the guide to decision making, that have been translated into the two hypotheses set out in Chapter VI (Food Consumption Risks) (Hypothesis 1: Clones are the same as sexually-derived animals, and Hypothesis 2: Clones are different from sexually-derived animals.)

This approach does not require that there be a set number of studies to make conclusions regarding the risks to animal health or food safety associated with cloning, and allows for the evaluation of asymmetrically sized data sets (i.e., data from the smaller data set on swine clones can be evaluated as rigorously as data from the larger data set on cattle clones). The narrative that accompanies each conclusion in the Risk Assessment provides an extremely transparent process for the reader to see how the agency drew its conclusions.

With respect to bias, we have already indicated the methods used to evaluate data sets. Our goal in evaluating the data on animal health, for example, was not to determine whether animals involved in the cloning process experienced adverse outcomes, but rather whether any of these outcomes are unique to cloning. The fact that our Draft Risk Assessment met with the approval of an external peer review group gives us confidence that our interpretation of the available data is justified.

Finally, with respect to the issue of requiring an additional Veterinary Medicine Advisory Committee (VMAC) meeting, the recommendations made by the VMAC in November of 2002 were instrumental in driving the expanded section on animal health and the appendices on adverse outcomes noted in other assisted reproductive technologies. We further note that the Draft Risk Assessment, the Proposed Risk Management Plan, and the Draft Guidance for Industry have been peer reviewed by an outside group of independent scientists, the chair of which was a member of the VMAC that had previously reviewed the agency draft Executive Summary of the Risk Assessment, and continues to serve on the existing VMAC to ensure that the VMAC’s concerns were addressed. Finally, the scientific and professional community with particular expertise in animal health (Federation of Animal Science Societies and American Veterinary Medicine Association) had the opportunity to review these documents during the open comment period, and has commented favorably on the agency’s methods and conclusions. We therefore believe that these documents have been subjected to sufficient external peer review and do not believe that we need to convene the current VMAC for additional review.

The public comments contained several general opinions on cloning. Some wished to emphasize that the sexually reproduced progeny of clones are not the same as clones, and should not be considered any differently from other sexually reproduced animals in livestock agriculture. Other comments agreed with the agency’s conclusion that cloning is another form of the assisted reproductive technologies currently in use in modern agriculture. Some comments opined that cloning could be useful to animal breeders by accelerating centuries’ old selection processes by introducing desirable traits into both breeding and production lines more rapidly. Some of the desirable traits that were mentioned included disease resistance, better conformation (the physical attributes of animals that promote health, longevity, and adaptation to certain environments or management conditions), and more predictable production of flavorful meat products. Other comments indicated that cloning would continue or add to the stress experienced by animals in production agriculture, and that cloning would more likely be used to increase milk production (and thus increase profits) than to increase disease resistance.

Agency Response to these Comments:

We agree that the sexually reproduced progeny of clones are not the same as clones and, based on data that we have reviewed, do not appear to manifest the same adverse outcomes observed in their parents. This is consistent with the biological assumptions that gametogenesis in clones resets aberrant epigenetic programming and that sexually reproduced progeny of clones should not display aberrant patterns of gene expression. Further, at this time, clones will be used as elite breeding animals and almost all of the meat or milk production animals derived from the cloning process will be the sexually reproduced offspring (progeny) of clones. We do note, however, that some milk from dairy clones may be introduced into the food supply, and once their utility as breeding animals is over, clones will also likely enter the food supply as meat. It is for these reasons that we conducted the food consumption risk assessment primarily on clones instead of on their progeny.

With respect to the introduction of desirable traits into breeding and production lines, and the nature of the traits that will likely be introduced, the agency does not regulate animal breeding or assisted reproductive technologies, and therefore does not have a position on this point. The agency considers cloning as another tool in the animal breeder’s toolbox: it can be used responsibly to introduce traits that benefit animal health (e.g., disease resistance or improved conformation) or human preferences (e.g., more tender meat) or not.

Effects of cloning on animal health were the subject of many of the public comments. In the Draft Risk Assessment, FDA concluded that cloning increases the risk of health problems in animals involved in the cloning process, particularly very young calf and lamb clones and their surrogate dams. Of the comments that addressed animal health risks, a small subset pointed out that although these risks exist, the observed health issues are not unique to cloning but also occur at lower frequencies when other assisted reproductive technologies (ARTs) are used. Many of these comments also pointed out that the lack of qualitative differences between health problems in clones and conventionally produced animals demonstrates that cloning falls on a continuum of ARTs currently used in livestock production. Also noted was the evidence that physiologically, clones that appear healthy are virtually indistinguishable from animals produced by conventional breeding.

Some comments thought it important to reemphasize that the progeny of clones are not clones themselves, but are the same as other sexually reproduced animals, and thus not affected by the health problems sometimes seen in clones. Several comments supported FDA’s exhaustive review of the available data on the health of animal clones and weight of evidence approach, and opined that the conclusions regarding animal health in the risk assessment were justified.

Many comments expressed concern regarding the adverse health outcomes described in the risk assessment. Concerns were raised regarding the low efficiency of the cloning process (i.e., the number of clones born relative to the number of fused embryos or embryos transferred to surrogate dams); effects on the surrogate dam and newborn fetus associated with Large Offspring Syndrome (LOS); congenital abnormalities in clones; and the lack of information on the longevity of clones and the health of multiple generations of their offspring. Also cited were premature deaths in clones, the assertion that there is no such thing as a healthy clone, and the possibility that greater numbers of sick animals due to cloning would increase the use of antibiotics and present new challenges for herd management.

The lack of unique health risks associated with cloning was considered by some as unimportant because any increase in the incidence of adverse health outcomes should be considered unacceptable regardless of the technology used. Many organizations with concerns about animal health felt that the agency’s analysis of the data was inaccurate and inappropriate because it relied too heavily on assumptions, too few studies, and/or unreliable data provided by clone producers. The general conclusions of these comments were that cloning causes undue animal suffering and has a significant negative impact on animal health and welfare. Some comments also criticized the proposed risk management plan as weak and inadequate to address animal health risks associated with cloning. The agency was urged to maintain a moratorium on cloning, accumulate more long-term data on the health of clones, and engage in more proactive efforts to address the adverse effects of cloning on animal health and welfare.

Agency Response to these comments:

The Animal Health component of the Cloning Risk Assessment was conducted at the FDA Center for Veterinary Medicine (CVM) by an integrated team of animal scientists, toxicologists, veterinarians, animal scientists, physiologists, molecular biologists, and risk assessment specialists. After careful and thorough analysis of the available data, this team identified and described in detail the animal health risks associated with cloning. Every effort was taken to make this science-based evaluation as objective as possible, and adverse health outcomes are described in the risk assessment with the same or greater level of detail as positive health outcomes. Some of the conclusions in the Draft Risk Assessment were based, in part, on previously unpublished data provided to FDA from commercial cloning companies. These data were considered important and useful because they provided extensive analyses of the health of cattle and swine clones that were much more detailed and comprehensive than those available in the published literature. Further, because these data were made available in “raw” unanalyzed form, the agency was able to carry out a much more detailed assessment of this information than they would be possible from the summary data presented in peer-reviewed journals. We also note that since release of the Draft, many of these data were published in peer-reviewed journals, including a review of the health of more than 350 bovine clones produced over a five year period. 1

Although the highest degree of animal health risk associated with cloning seems to occur in cattle and sheep as a result of LOS, it is important to point out that not all clone pregnancies are affected by LOS. In fact, most calf and lamb clones are born healthy, grow and reproduce normally, and are no more susceptible to health problems than their non-clone counterparts. In swine and goats, cloning-associated abnormalities are far less common than in cattle and sheep; LOS is not observed in these species, and the vast majority of pig and goat clones are born healthy without subsequent health problems.

As explained in the risk assessment and reiterated in some of the comments, cloning falls on a continuum of ARTs that includes artificial insemination, in vitro fertilization, embryo transfer, and embryo splitting. All of these technologies are tools that have allowed farmers to accelerate the propagation of genetically superior animals to provide the public with meat and milk that is safe, wholesome, and of consistent quality. The adverse outcomes associated with cloning are not unique but are also observed, at lower frequencies, with other ARTs in which embryos are produced in vitro. FDA does not regulate any of the ARTs used in livestock production, and therefore, there is no reason for FDA to impose specific restrictions on livestock cloning, particularly in light of the agency’s conclusion that foods derived from these animals are as safe as food from their conventional counterparts.

Another important distinction is that the progeny of clones are not clones themselves, but are produced by sexual reproduction just like any other conventionally bred animal. All of the studies describing the progeny of clones indicate that these animals are entirely normal and, unlike their clone parents, are not at increased risk of health problems. These observations provide strong support for the hypothesis that health abnormalities experienced by clones are the result of epigenetic changes that are unique to each clone, and that neither these changes nor the associated anomalies are passed down to their offspring.

FDA neither supports nor opposes cloning. Consistent with CVM’s mission of fostering animal health, however, the agency shares the concerns voiced in many of the public opinions regarding the increased incidence of adverse health outcomes in clones and recognizes the importance of mitigating these risks. As described in the Risk Management Plan, FDA is addressing the animal health risks associated with cloning by establishing working relationships with professional societies dedicated to the health and care of food-producing animals. With active encouragement from FDA, these societies are developing detailed standards of care specifically designed to minimize the frequency and impact of risks to the health of animals involved in the cloning process. FDA is committed to promoting effective communication of these standards of care to clone producers.

As it is in the best interest of livestock producers to minimize both the incidence and severity of health problems in their animals, the agency does not anticipate that the adverse health outcomes that have been observed during the early stages of development of this technology will be commonplace on farms in the future.

With respect to food consumption risks, the overall conclusion of the Draft Risk Assessment was that foods produced by animal clones are as safe as foods produced by conventionally bred food animals. Some of the public comments supported this conclusion, and remarked that FDA’s two-pronged strategy (animal health and compositional analysis) to assess food consumption risks was thorough and justified. From the perspective of animal health, many agreed with the premise that if an animal is healthy, it will likely produce safe food. Many also agreed that the existing food inspection methods and standards would effectively prevent the entry of unhealthy clones into the food supply. Regarding the data on the composition of foods from clones versus non-clones, it was pointed out that no significant compositional differences had been reported. Although some studies indicate that values for certain components of meat and milk may be quite variable among clones, these values do not fall outside the normally diverse range of corresponding values found in meat and milk from conventional animals and thus do not pose a human food safety concern.

In contrast, other comments questioned the validity of FDA’s conclusion regarding food consumption risks. A number of these comments cited a paucity of studies on the safety of foods from clones, particularly peer-reviewed studies. Concerns included possible potential toxicity, allergenicity, or alterations in the nutritional quality of milk or meat from clones.

Many comments indicated a need for more thorough and long-term testing of foods from clones to identify and characterize potential food consumption hazards created by the cloning process and identify the public health consequences of consuming these foods. Also noted was the lack of multi-generational studies in clones to search for the presence of unexpected metabolites or mutations that could be passed on to progeny and affect food safety. Some organizations predict that such changes could lead to a general decrease in milk consumption, which in turn could cause nutritional deficits in the human population and have a detrimental effect on federal nutritional goals.

With respect to the animal health component of FDA’s food safety analysis, some comments pointed out that no data were provided in the risk assessment to support FDA’s premise that healthy animals will produce healthy foods. Also questioned was the capacity of existing food safety inspection systems to detect clones suffering from health problems and prevent them from entering the food supply. Suggested remedies for such problems included an animal identification system for clones and strict post-market control points for their entry into the food supply. Several comments discussed the possibility that unhealthy clones might produce more pathogenic bacteria and shed them in their feces, thereby increasing the risk of foodborne pathogens.

Agency Response to these comments:

As previously described, when FDA first undertook this analysis, there were no risk assessment methods available to assess the safety of food from clones, nor were there many data on clones. In developing our risk assessment methodology, we asked how hazards that could pose food consumption risks be introduced to animals that had been produced by somatic cell nuclear transfer. We concluded that the only pathway for hazards to arise was via the inappropriate expression of genes that were already present in these animals. In order to detect whether such hazards had indeed been introduced, we returned to the principles that have been traditionally used to assess the safety of meat and milk from animals produced via any type of reproduction, as the possibility for the aberrant expression of inherent genes would exist for those animals as well. These include the complementary steps of evaluating the health of the animal, and the composition of the food from the animal. Thus, the two-pronged approach used in the risk assessment was developed.

As is the case for all risk assessments, the number of studies and amount of data available for each endpoint in this analysis was variable; we accommodated for the asymmetrical size of the data sets by using a weight of evidence approach (described in Section B of these Responses). Conclusions regarding food consumption risks for each of the four species were formulated using a rigorous weight of evidence approach that carefully evaluated the empirical (scientific) evidence; determined the extent to which the data supported each other; and considered whether the observations were consistent with known biological mechanisms and principles. The weight of evidence approach does not require a specific number of studies on any particular endpoint in order to be valid. Instead, all of the information is considered together in one framework. This approach allowed the agency to perform a qualitative assessment of the risks associated with consuming meat or milk from animal clones or their progeny. Furthermore, the weight of evidence approach allowed for the identification of uncertainties and provided a science-based path for further investigations to resolve those uncertainties. These uncertainties are clearly noted in the Risk Assessment. In the case of foods from sheep clones, uncertainties related to the lack of empirical data precluded the assessment of food consumption risks.

We note that at the time we concluded our review of the data in the Draft Risk Assessment, the number of studies describing the composition of meat and milk from clones and their progeny was limited. Since the publication of the Draft, several additional studies describing the composition of food from clones have become available, some of which were identified by the public comments. FDA has reviewed several studies that describe in detail the fatty acid and amino acid composition of meat and milk from clones, as well as their vitamin and mineral content. The results of these studies consistently indicate that the compositions of foods from clones are not materially different from foods we eat everyday, and thus strengthen the conclusions of the Draft Risk Assessment that foods produced by cattle, swine, and goat clones are as safe as foods from conventionally produced animals.

All indications point to the use of clones themselves as elite breeding stock; as such their numbers would be small, and they would comprise only a small proportion of the animals in US herds. Thus the contribution of meat and milk derived directly from clones in the food supply will be extremely limited. Instead, the progeny of clones are expected to be the production animals from which meat and milk would be produced. We reiterate the importance of understanding that the sexually reproduced progeny of clones are not clones, but are the same as any other sexually reproduced animals. This conclusion was first expressed in the 2002 report by the National Academies of Sciences report “Animal Biotechnology: Science Based Concerns,”2 and has been confirmed by carefully consideration of the underlying biological mechanisms at work in both SCNT and sexual reproduction, as well as empirical studies of the progeny of cattle and swine clones. For example, in a comprehensive study that was reviewed for the Draft Risk Assessment and has since been published in a peer-reviewed journal,3 the composition of meat from 242 progeny of swine clones was not found to be materially different from meat from conventionally produced pigs. The lack of food consumption risks from meat or milk from progeny of clones is further supported by the health data from these sexually produced animals, which indicates that they are born healthy, grow and reproduce normally, and do not display the increased frequency of anomalies observed in some of their clone parents.

With respect to detecting anomalies in clones, we note that clones will be subject to the same pre- and post-mortem inspections as conventionally bred food animals. Because the same anomalies are found in clones as are found in animals bred by other assisted reproductive technologies, no special post-market control points for clones are necessary.

FDA found no evidence to indicate that foods from clones pose an increased allergenic risk. No novel proteins have been identified in meat or milk from clones, and studies using animal models have not indicated that the allergenic potential of meat or milk from clones is increased relative to meat or milk from conventional animals. Moreover, feeding studies in rodents have not revealed any physiological effects of consuming meat or milk from clones. These findings are consistent with our conclusions from the analysis of food composition and animal health data, i.e., that foods from clones and their progeny are not materially different from meat and milk derived from conventional counterparts and thus do not pose any additional food consumption risks relative to foods from conventional animals.

The FDA is not aware of any studies that have addressed the question of whether clones shed more pathogenic bacteria in their feces. However, the data reviewed in this risk assessment indicate that the vast majority of clones studied during the juvenile, reproductive, and post-pubertal phases of life are as healthy as their sexually-produced counterparts. There is no biological reason to indicate that healthy clones (i.e., clones entering the food supply) would shed any more pathogens into their feces than other healthy livestock. It is therefore unlikely that the risk of foodborne pathogens due to contamination of carcasses with fecal bacteria would pose a greater food consumption risk in clones compared with conventionally bred food animals. Further, we note again, that clones are not expected to contribute to the food supply in any significant number; rather the sexually reproduced offspring of clones, which are the same as any other sexually reproduced animals, would comprise almost all of the animals producing food.

Of the comments addressing the effects of cloning on genetic diversity, most expressed the concern that cloning would decrease genetic diversity of livestock breeds, making herds more susceptible to infectious or other types of diseases. The assumption that appears to be at the root of this argument is that cloning would become so widely used that most of the animals in the national herds of cattle, swine, or goats would either be clones, or be so immediately descended from clones as to carry a particular genotype. Others commented more favorably on the ability to identify and tailor genetic pools for specific environments (e.g., genes that allow cattle to thrive in hot, dry climates). Still others opined that the introduction of the genomes of steers (castrated male cattle incapable of sexual reproduction) with known phenotypes by using somatic cells as nuclear donors for cloning could actually expand the genetics of herds by propagating those desirable traits.

Agency Response to these Comments:

As previously discussed, FDA does not regulate animal breeding, so we have no position on the points raised in the comments. Nonetheless, we reiterate the statement made previously that cloning is a tool in the animal breeders’ toolbox: it can be used responsibly to introduce desirable traits or not. Responsible breeders rely on careful observation of the performance of offspring to determine whether their breeding choices have been successful; such observations and strategic breeding practices have led to significant improvements in animal health and productivity over the past half century. We assume that breeders will continue to breed livestock responsibly.

Consumer acceptance and the role of communications were very evident in the public comments. Many comments strongly urged the agency to provide more consumer education, while others advocated more public polls and consumer surveys. Many cited existing polls as evidence of the public’s lack of acceptance of cloning and food from clones, and stated that based solely on consumer opinion, the agency should not “approve” clones. In contrast, others concluded that it is too early to draw firm conclusions from polls as to whether clones or their products will be accepted by US consumers, largely due to the public’s general lack of knowledge of animal breeding and agricultural practices.

Some groups opined that lifting the voluntary ban on food from clones would shake consumer confidence in the agency or safety of the food supply, including predictions of changes in dietary habits (e.g., refusal to purchase any dairy products for fear that they might be derived from clones) that ultimately would result in dietary risks.

Agency Response to these Comments:

The agency notes that there has been a great deal of discussion regarding consumer acceptance of cloning, including reliance on the results of various polls. Initial review of many of these polls indicates that segments of the US population do not favor cloning. We believe that closer review reveals that the public is, in fact, unsure about how they feel about cloning or the safety of food from clones. We also note that public acceptance appears to be largely influenced by unrealistic representations of clones in science fiction novels or movies.

We found compelling an academic study of polls and public opinion on cloning submitted as part of the public comment process (EC- 8253) that showed that peoples’ opinions on this topic were likely to change over time, especially in response to new information. This comment reported that opinions can change over the 10-15 minute period during which a survey is conducted if information on the topic is provided. Given that the public is largely naïve with respect to cloning and other reproductive strategies used in agriculture, we believe that the predicted consumer behavior based on polls cited in many of the public comments may be less accurate than some have purported. In support of this position, we cite the speculations, based on polling in 1992, of decreased milk consumption if the FDA approved recombinant bovine somatotropin (rBST). In fact, fluid milk consumption did not decline but remained steady in the year following approval of rBST, based on a formal study performed by USDA’s Agricultural Research Service.

Finally, we note that the agency’s main regulatory objective throughout this risk assessment process has been to determine whether there are any food safety risks from clones and their progeny and to protect the public health. The agency understands that there are strong public views on matters such as animal cloning and recognizes the importance of providing the public with an unbiased source of information about agricultural cloning so that individuals can make informed decisions based on facts. To that end, we remind the public that the agency has posted a series of communication pieces on cloning on its website to help assuage some of these concerns.

Labeling was the subject of many of the public comments in both the substantive and more general comments. Most of the commentators, particularly in the general comments, indicated that the agency should require labeling of foods from clones to give consumers a choice as to whether they want to consume food from clones or not. The need for labeling for purposes of consumer choice was also expressed in many of the substantive comments.

Another sizable proportion of the comments urged the agency not to label food from clones or their progeny; some of these comments included a formal analysis of the statutory authorities and case law regarding labeling of food products. Several comments requested clarification of the agency’s position on negative labeling—that is, language that would be acceptable to indicate that meat or milk did not come from clones or their progeny, including the possibility of issuing Guidance for Industry on that topic.

Others expressed the opinion that the agency should not use a double standard to require labeling on animal clones or their food products, while none would be required for plant clones (i.e.,fruits and vegetables that are reproduced asexually such as bananas and potatoes).

Comments from individuals who self-identified with various organizations associated with the organic community uniformly commented that clones and cloning were not compatible with organic standards and philosophy.

Agency responses to these comments:

Under the Federal Food, Drug, and Cosmetic Act, a food is misbranded if its labeling is false or misleading. Also, under the Act, in determining if labeling is misleading, the agency is to consider whether the labeling fails to reveal material facts. Because the risk assessment process has clearly shown that there are no food safety concerns for the meat and milk from cattle, swine, and goat clones and the progeny of all clones and that meat and milk from cattle, swine, and goat clones and the progeny of all clones are not materially different from their conventional counterparts, we do not believe, at this time, that there is a material fact that would be required to be included in the labeling of these foods based on the fact they are from clones or the progeny of clones.

With respect to “negative labeling”, the agency notes that all food labels must be truthful and not misleading. We would determine on a case-by-case basis whether any negative labeling was false or misleading. At this time, we do not anticipate issuing any further guidance on this issue.

Finally, the agency notes that because representatives of the organic food community are uniform in their opinion that cloning is not compatible with organic principles, consumers who do not wish to consume food from clones may exercise their choice by purchasing food that has been certified organic. We repeat, however, our conclusion that food from clones or their progeny is as safe as food we eat every day.

Potential economic impacts of cloning were discussed in many of the public comments. A few comments predicted that cloning might provide economic benefits to livestock breeders and producers by allowing them to expand the numbers of genetically superior animals more rapidly than is possible with currently available breeding technologies. Cloning was also seen by some as compatible with the goal of raising the most productive, healthiest possible food animals that produce safe and affordable milk and meat. Other comments expressed the opinion that the competitive advantage of US producers and processors in domestic and world markets depends on continued support and encouragement of technological advancements in animal agriculture.

In contrast, many of the public comments predicted that release of food products from cloned cattle into the food supply would have detrimental economic effects, particularly on the US dairy industry. A major concern in this group of comments was a projected 15% drop in sales of fluid milk. This projection was based on consumer polls indicating a lack of consumer confidence in the safety of foods from animal clones and their progeny. (Associated with this lack of consumer acceptance was the prediction of a substantial shift in dietary patterns leading to negative public health consequences.) A few organizations opined that the benefits of cloning would go only to the investors and large corporate farms but provide no benefit to the consumer, and would impose particular hardships on family farms with fewer resources available to clone animals. Also projected as a result of releasing milk from cattle clones into the food supply were major impacts on international trade of dairy products, including the risk of losing significant markets for US dairy exports.

A few comments recognized the potential economic impacts of cloning, but pointed out regulation of these impacts is not under FDA’s regulatory purview. Most of the comments expressing economic concerns, however, called for FDA to conduct a full cost-benefit economic analysis of the releasing milk from clones into the food supply. Many voiced the opinion that it is also FDA’s responsibility to conduct additional consumer research and ensure that consumers will accept milk from clones and their progeny before lifting the voluntary moratorium. With respect to international trade, it was suggested that FDA participate in additional, transparent public discourse on cloning, including an international dialogue to facilitate global introduction of technology, harmonize regulatory processes among countries, and avoid potential trade disputes.

Agency Response to these comments:

FDA is responsible for protecting the public health by assuring the safety of the nation’s food supply. FDA’s mission also includes communication of accurate, science-based information to the public (http://www.fda.gov/opacom/morechoices/mission.html). With respect to food from clones, both of these responsibilities have been fulfilled by conducting the risk assessment and releasing its results, together with the accompanying guidance and risk management plan, to the public. It is not, however, FDA’s responsibility to assess potential economic impacts of its regulated products, including foods, being released into commerce. The decision to use cloning technology in food producing animals will be up to the individual producer. As many of the public comments have noted, consumer choice will dictate whether cloning is an economically viable option for livestock producers. Similar to potential economic impacts, it is not FDA’s responsibility to ensure that consumer accept foods made with new technologies. Instead, it is the agency’s responsibility to provide consumers with accurate, science-based information that will allow them to make informed choices regarding the safety of foods they consume.

Many of the general and substantive comments discussed ethical issues associated with animal cloning, and some strongly encouraged the agency to address these issues. Most of the ethical concerns were based on the adverse health outcomes observed in some clones and their surrogate dams, although another group was concerned about the implications of agricultural cloning for human cloning. A subset of these comments stated that such considerations should occur prior to the agency’s issuing a final version of the cloning documents and suggested various venues for discussion, such as a Department-level committee. With equally strong sentiment, other comments opined that it was not the agency’s responsibility or within its authority to address ethical issues.

Agency Response to these Comments:

Although FDA appreciates that some members of the public have strong opinions on this topic, the agency has not been charged with addressing moral, religious, or ethical issues associated with animal cloning for agricultural purposes. We have attended several public conferences that addressed these types of ethical concerns as well as those regarding animal health related to animal cloning for agricultural purposes to ensure that the discussions are based on factually correct scientific statements, and we will continue to do so.

Many of the concerns regarding the moral, religious, or ethical issues of animal cloning for agricultural purposes are equally applicable to other methods of animal breeding and management, and have been the subject of many scholarly discussions and publications. Because cloning falls on a continuum of other assisted reproductive technologies, we believe that discussions on these ethical concerns about animal cloning for agricultural purposes should be held in the larger context of these assisted reproductive technologies.

With regard to ethical concerns related to animal health, as we have stated in our response to the public comments regarding animal health, we have taken a leadership role in developing a set of animal care standards for clones. These standards are designed to provide clone producers with information from experts in the fields of assisted reproductive technologies and animal health to help minimize the potential for adverse outcomes in livestock clones, and will be released by the sponsoring organization, the International Embryo Transfer Society, in 2008.